2 order to maximize good outcomes. Fortunately, the majority of jaundiced patients have a more indolent course and the emergency physician serves as a facilitator in the diagnostic work-up, initiating management and ensuring that an appropriate disposition is made. Whether jaundice is the presenting complaint or an incidental physical finding, it requires the emergency physician (EP) to be an astute diagnostician. Because the differential is so broad, a thorough history and physical examination must be performed a challenge in even a moderately busy department. The history and physical examination will help narrow the differential diagnoses, driving the work-up and disposition. This issue of Emergency Medicine Practice will focus on the challenge of evaluating and treating the jaundiced patient in the emergency department using the best available evidence from the literature. The clinical pathway provided can be used as a quick reference to help facilitate caring for these patients. Critical Appraisal Of The Literature A literature search was performed using Ovid MED- LINE and PubMed from 1950 to the present. The areas of focus were acute liver failure, obstructive jaundice, neonatal hyperbilirubinemia, hemolysis, and cholangitis. Terms used in the search included jaundice, icterus, hyperbilirubinemia, obstructive jaundice, acute/fulminant liver failure, and neonatal jaundice. Over 300 articles were reviewed, which provided background for further literature review. The Cochrane Database of Systematic Reviews and the National Guideline Clearinghouse (www.guidelines.gov) were also consulted. Table 1 lists those guidelines related to jaundice that are helpful for the practicing emergency physician. Etiology And Pathophysiology Jaundice is the physical manifestation of elevated serum bilirubin. The normal serum concentration of bilirubin is less than 1 mg/dl (17 μmol/l). 1 Typically, jaundice is not detectable clinically until serum bilirubin reaches 2.5 mg/dl. 2 It is first seen in the conjunctiva or oral mucous membranes such as the hard palate or under the tongue. As the serum concentration of bilirubin rises, jaundice proceeds caudally. Bilirubin deposition is usually benign, but in neonates, unconjugated bilirubin can cross the blood-brain barrier and deposit in the basal ganglia. Encephalopathy becomes a concern at levels of mg/dl. Comprehending normal bilirubin metabolism is crucial to understanding the pathologic conditions that cause jaundice. Bilirubin is derived from the Table 1. Published Guidelines Organization Topic Type Of Guideline Recommendations American College of Radiology 32 Imaging for patients with jaundice Evidence-based 1. Ultrasound (US) is recommended in cases of suspected benign obstruction. 2. CT is recommended initially for suspected malignant obstruction. 3. US is recommended for patients with low likelihood of mechanical obstruction. 4. CT is recommended for patients with indeterminate suspicion of mechanical obstruction. American Society for Gastrointestinal Endoscopy 65 Choledocholithiasis Evidence-based US is the initial imaging modality for evaluation of suspected choledocholithiasis. American Society for Gastrointestinal Endoscopy 66 The role of endoscopic retrograde cholangiopancreatography (ERCP) in pancreatic and biliary diseases Evidence-based 1. ERCP is primarily a therapeutic procedure. 2. Diagnostic ERCP should not be undertaken in the absence of objective findings of obstruction from other imaging modalities. 3. ERCP is recommended for: a. Post-operative biliary leaks or strictures. b. Acute or chronic pancreatitis. c. Palliation of malignant biliary obstruction. d. Pancreatic duct stones or leaks. e. Drainage of pancreatic pseudocysts. f. Diagnosis of pancreatic malignancies. 4. ERCP is not recommended prior to routine laparoscopic cholecystectomy. 5. ERCP is safe in children and pregnancy. American Academy of Pediatrics 104 Neonatal jaundice and kernicterus Consensus 1. Any infant who is jaundiced before 24 hours of age requires measurement of serum bilirubin level and evaluation for hemolytic disease if elevated. 2. All neonates discharged before 48 hours of life should be rechecked in two to three days. 3. Risk factors for severe hyperbilirubinemia should be assessed to determine timing of further follow-up. 4. Support should be offered for breastfeeding mothers. Emergency Medicine Practice 2 March 2008 EBMedicine.net

3 breakdown of heme molecules; the majority (80%) is from senescent red blood cells (RBCs). The remaining 20% comes from other heme-containing proteins. 3 The reticuloendothelial cells of the liver and spleen destroy the RBCs, releasing unconjugated bilirubin into the circulation. While in circulation, bilirubin is bound to albumin and enters hepatocytes passively, where it undergoes glucuronidation by a family of enzymes called uridinediphospho-glucuronosyltransferases (UGT). The conjugated bilirubin molecules are actively transported across the canalicular membranes into the biliary system. This is detailed in Figure 1. Bilirubin is stored as part of bile in the gallbladder and emptied into the duodenum. In the colon, the majority is metabolized to stercobilin or urobilinogen by colonic bacteria. Stercobilin is excreted in the stool. Urobilinogen is reabsorbed into the bloodstream and excreted in the urine. The remainder of conjugated bilirubin in the gut is de-conjugated and taken up by intestinal epithelial cells. From there, it enters the portal circulation and returns to the liver (enterohepatic circulation). Conjugated bilirubin can also enter circulation from diffusion out of the hepatocytes. Once in circulation, it is filtered by the glomerulus and then reabsorbed so that no direct bilirubin is excreted under normal conditions. When the filtered load of direct bilirubin exceeds the tubular absorptive capacity, direct bilirubin appears in the urine. Thus glomerular filtration plays a role in determining serum levels of direct bilirubin, and patients who have both liver disease and renal insufficiency can have extraordinarily high bilirubin levels. In the laboratory, conjugated bilirubin is the fraction that reacts directly with the reagents. Thus it is reported as direct bilirubin. The unconjugated fraction requires the addition of an accelerator compound and is referred to as indirect bilirubin. 3 There is an extensive differential diagnosis for hyperbilirubinemia that is initially narrowed by identifying the fraction of bilirubin that is elevated (direct versus indirect). For primarily direct hyperbilirubinemia, potential causes are further divided into cholestatic Figure 1. Bilirubin Conjugation versus hepatocellular injury patterns based on the liver function tests. Conditions Causing Indirect Hyperbilirubinemia There are three basic pathophysiologic mechanisms that lead to indirect hyperbilirubinemia: overproduction of bilirubin, impaired bilirubin uptake, and impaired conjugation. Neonatal jaundice combines all three of these mechanisms. Causes of indirect hyperbilirubinemia are presented in Table 2. Overproduction Of Bilirubin Overproduction of bilirubin is due to decreased synthesis or increased destruction (hemolysis) of RBCs. The differential diagnosis for hemolytic anemia is listed in Table 3. Decreased RBC synthesis occurs in various anemias (iron deficiency, megaloblastic, and sideroblastic) and lead poisoning. In these conditions, the reticuloendothelial cells of the bone marrow degrade heme molecules that are not incorporated into RBCs. Impaired Bilirubin Uptake Conditions that cause decreased hepatic circulation, such as congestive heart failure or portosystemic shunts, can lead to decreased bilirubin uptake in the Table 2. Causes Of Indirect Hyperbilirubinemia Increased bilirubin production Impaired hepatic bilirubin uptake Impaired bilirubin conjugation Table 3. Causes Of Hemolysis Hemolysis (intravascular or extravascular) Impaired RBC synthesis (megaloblastic, sideroblastic, iron deficiency anemia, lead poisoning) Congestive heart failure Portosystemic shunts Drugs (rifampin, probenecid) Crigler-Najjar syndrome Gilbert s syndrome Neonates Hyperthyroidism Ethinyl estradiol Liver diseases (chronic persistent hepatitis, advanced cirrhosis, Wilson s disease) Courtesy of Matthew Wheatley, M.D. and Suzanne Hardy. Congenital Acquired Hereditary spherocytosis Glucose-6-phosphate dehydrogenase deficiency (G6PD) Sickle cell disease Autoimmune Cold and warm agglutinins Drug-induced Microangiopathic hemolytic anemia (MAHA), disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS) Paroxysmal nocturnal hemoglobinuria (PNH) Mechanical valve EBMedicine.net March Emergency Medicine Practice

4 sinusoids. Cirrhosis, Gilbert s syndrome, and drugs such as rifampin or probenecid can have the same effect. Impaired Conjugation Impaired conjugation results from impaired or absent UGT in the hepatocytes. Inherited causes for this include Gilbert s syndrome and Crigler-Najjar syndrome. Neonatal jaundice results, in part, from the fact that conjugation capacity of the neonatal liver is easily overwhelmed. Acquired causes include hormonal modulation (hyperthyroidism and ethinyl estradiol), antibiotics (gentamycin, novobiocin), and liver disease (chronic hepatitis, cirrhosis, and Wilson s disease). Conditions Causing Direct Hyperbilirubinemia There are multiple acquired and inherited causes for direct hyperbilirubinemia. Inherited causes are quite rare and will affect neonates. The most familiar causes are the Dubin-Johnson and Rotor syndromes. The former affects the biliary excretion of organic anions while the latter is a disorder of hepatic storage of bilirubin. Both are benign syndromes that have fluctuating elevations of both conjugated and unconjugated hyperbilirubinemia. Additionally, there are other conditions, progressive familial intrahepatic cholestasis, and benign recurrent intrahepatic cholestasis that cause a conjugated hyperbilirubinemia as a result of reduced bile flow. 4 Acquired conditions can be divided into biliary obstruction, intrahepatic cholestasis, and hepatocellular injury. Both inherited and acquired causes are summarized in Table 4. Extrahepatic Biliary Obstruction Extrahepatic biliary obstruction can lead to both a conjugated and unconjugated hyperbilirubinemia. As conjugated bilirubin increases in the hepatocytes, glucuronidation is reversed and some of the unconjugated bilirubin leaks into the plasma. Alkaline Table 4. Causes Of Direct Hyperbilirubinemia Extrahepatic cholestasis (biliary obstruction) Intrahepatic cholestasis Hepatocellular injury See Table 7 Choledocholithiasis Intrinsic and extrinsic tumors Primary sclerosing cholangitis AIDS cholangiopathy Acute or chronic pancreatitis Strictures Parasitic infections Viral hepatitis Alcoholic hepatitis Non-alcoholic steatohepatitis Primary biliary cirrhosis Drugs and toxins Sepsis/hypoperfusion Infiltrative diseases Total parenteral nutrition Pregnancy Cirrhosis phosphatase (AP) and gamma-glutammyl-transferase (GGT) are also elevated due to dilated biliary ducts. The differential diagnosis is provided in Table 5 and includes cholelithiasis, tumors, infectious causes, pancreatitis, primary sclerosing cholangitis, and strictures. Gallstones can directly or indirectly obstruct extrahepatic bile ducts; an example is the Mirizzi syndrome where an impacted cystic duct stone causes gallbladder distension and leads to hepatic duct compression. Both intrinsic and extrinsic tumors can lead to extrahepatic cholestasis. Common causes are pancreatic carcinoma, hepatocellular carcinoma (HCC), cholangiocarcinoma, and metastatic disease. Infectious causes can include ascending cholangitis, parasitic infections, and AIDS cholangiopathy. Parasites include Ascaris lumbricoides (which migrates into the bile ducts from the intestines) and liver flukes (such as Clonorchis sinensis which lay eggs in the smaller bile ducts). Cryptosporidium, cytomegalovirus, and HIV most commonly cause AIDS cholangiopathy. 5 Intrahepatic Cholestasis There are a number of conditions that lead to intrahepatic cholestasis either primarily or as a result of hepatocellular injury. Please refer to Table 6 for a complete list. These patients usually present in a similar fashion to extrahepatic obstruction but have patent bile ducts. Hepatocellular Injury A list of conditions causing hepatocellular injury is provided in Table 7. There is considerable overlap between these conditions and those that cause intrahepatic cholestasis. This is due to the variable presentation and natural progression of many of these diseases. The primary mechanism can be distinguished based on the level of elevation of the various hepatic markers. Elevation of transaminases relative to bilirubin and alkaline phosphatase favors a hepatocellular injury pattern whereas elevation of bilirubin and alkaline phosphatase relative to transaminases favors a cholestatic picture. Table 5. Causes Of Extrahepatic Cholestasis Tumors Infection Cholangiopathy Pancreatitis Cholangiocarcinoma Pancreatic carcinoma Periampullary carcinoma Metastatic disease AIDS cholangiopathy cytomegalovirus (CMV), Cryptosporidium spp, HIV Parasitic infection Ascaris lumbricoides Choledocholithiasis Biliary stricture Primary sclerosing cholangitis Sphincter of Oddi dysfunction Acute or chronic Emergency Medicine Practice 4 March 2008 EBMedicine.net

6 causes of jaundice (Table 8) and to provide an appropriate work-up for non-emergent cases. The critical and emergent causes of jaundice include massive hemolysis, acute cholangitis, fulminant liver failure, acute fatty liver of pregnancy, and neonatal hyperbilirubinemia. These cases require emergent stabilization and therapeutic measures in the ED. Clues to a potentially critical patient with jaundice include altered mental status, fever, abdominal pain, bleeding, or hypotension. A patient with the triad of jaundice, right upper quadrant (RUQ) pain, and fever has acute cholangitis until proven otherwise. This collection of signs and symptoms is known as Charcot s triad and occurs in 50-75% of patients with acute cholangitis. 10 Patients with acute suppurative cholangitis may be septic with altered mental status and hypotension (Reynold s pentad). It is associated with increased morbidity and mortality. 11 Bacteria can enter the biliary system through several mechanisms such as retrograde ascent from the duodenum, invasion from the portal venous system, or mechanical disruption from endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous drainage. Stents and gallstones can also serve as a nidus of infection. E. coli, Klebsiella spp, Enterobacter spp, and Enterococcus spp are the most common bacteria. Anaerobes are fairly uncommon. 12 A jaundiced patient with elevated transaminases, encephalopathy, and coagulopathy is considered to have acute liver failure (ALF). If encephalopathy develops within eight weeks of the onset of illness, the condition is referred to as fulminant hepatic failure, whereas patients who develop encephalopathy in 8-26 weeks are said to have sub-fulminant failure. These patients are typically very ill at presentation and require close monitoring while in the emergency department. The mortality approaches 80%. 13 Traditionally, the most common cause of ALF in the U.S. has been viral hepatitis, with acetaminophen (APAP) toxicity being second; however, a recent prospective study showed that APAP toxicity has overtaken viral hepatitis as the most common cause, reflecting patterns seen in the United Kingdom. 14 Prehospital Care Few patients with jaundice have specific care needs in the prehospital environment. While universal precautions apply to all patient care, special attention is required in patients with jaundice secondary to viral hepatitis. No special decontamination procedures are Table 8. Life-Threatening Conditions Presenting With Jaundice Fulminant hepatic failure Acute cholangitis Massive hemolysis Neonatal hyperbilirubinemia - kernicterus Acute fatty liver of pregnancy required for a patient with suspected or known viral hepatitis following transport. Soiled linens and surfaces should be cleaned in the usual way prior to transport of the next patient. Unstable patients with jaundice may have an infectious or surgical emergency. Communication with medical control may ensure that the patient is transported to a center with the appropriate resources. For example, in large communities with tertiary medical centers, an overdose patient with jaundice at risk for acetaminophen-related hepatic failure might be best served by transport to a liver transplant center. ED Evaluation Initial Stabilization The necessity of stabilization measures depends on the underlying disease. Most patients will be clinically stable. However, patients with fulminant liver failure may be obtunded, coagulopathic, and hypotensive. Those with ascending cholangitis may be septic at presentation. Direct any patient who is hypotensive or obtunded to a resuscitation room for immediate intervention. Intubate patients with unstable airways. Treat hypotension with intravenous (IV) crystalloid bolus through large bore IVs, and establish central access if adequate IV access is not possible. However, due to the potential for coagulopathy, only attempt central access at compressible sites. Patients with normal vital signs and mental status can be given a lower priority. Due to the need for laboratory evaluation in most patients as well as the possibility of imaging, patients with jaundice are not appropriate for the fast-track portion of the ED. History A careful history and physical examination are essential in narrowing the differential diagnosis. A prospective series of 220 patients with jaundice and/or cholestasis found history and physical examination to be 86% sensitive in identifying intrahepatic versus extrahepatic disease. 15 In addition to jaundice, patients may also complain of pruritis or constitutional symptoms such as malaise, nausea, and anorexia as a result of the elevated serum bilirubin. Other complaints may include recent weight loss or increased abdominal girth from ascites. Important historical questions include time of onset, presence or absence of pain (quality, location, and radiation), fever, history of abdominal surgeries, birth history for neonates, medication history (especially the amount and time acetaminophen was taken), herbal medications, social history (including alcohol consumption, HIV and hepatitis risk factors, drug use, exposure to toxic substances or mushrooms, travel history, work history, and recreational history), and family history (including history of inherited diseases of liver or hemolytic disorders) (Table 9). Emergency Medicine Practice 6 March 2008 EBMedicine.net

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